Original ArticlesClinical Nephrology

Mycophenolate Mofetil for Induction and Maintenance of Remission in Microscopic Polyangiitis with Mild to Moderate Renal Involvement—A Prospective, Open-Label Pilot Trial

Francisco Silva, Ulrich Specks, Sanjay Kalra, Marie C. Hogan, Nelson Leung, Sanjeev Sethi and Fernando C. Fervenza
CJASN March 2010, 5 (3) 445-453; DOI: https://doi.org/10.2215/CJN.06010809

Abstract

Background and objectives: Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), often targeting myeloperoxidase (MPO). Cyclophosphamide (CYC) plus corticosteroids (CS) is considered standard therapy for patients with renal involvement, but treatment response is not satisfactory in all patients and CYC has well recognized toxicity. This prospective pilot trial explored whether mycophenolate mofetil (MMF) represents an effective alternative to CYC for induction and maintenance of remission in MPA with mild to moderate renal involvement.

Design, setting, participants, & measurements: Seventeen P-ANCA/MPO-ANCA-positive patients with MPA with mild to moderate renal involvement received MMF (1000 mg orally, twice daily) and CS (intravenous methylprednisolone, 1 to 3 g, followed by oral prednisone at 1 mg/kg per day). Oral CS were discontinued by month 6; MMF was continued through month 18. The primary outcome measure was remission by month 6 and stable renal function. Secondary endpoints included major relapses necessitating a switch to CYC plus CS, minor relapses requiring an increase in CS dosage, and adverse events.

Results: Thirteen of 17 patients enrolled achieved the primary outcome, and 4 failed because of insufficient response, relapse, or MMF intolerance. Twelve patients remained in remission through month 18, renal function remained stable, and proteinuria improved. Side effects of MMF were mild, transient, and responsive to dose adjustments in all patients except one.

Conclusions: MMF represents an alternative to CYC for induction and maintenance of remission in patients with MPO-ANCA-associated MPA with mild to moderate renal disease.

Microscopic polyangiitis (MPA) is a small- to medium-size vessel vasculitis frequently associated with a pauci-immune necrotizing GN and pulmonary capillaritis (1). Anti-neutrophil cytoplasmic antibodies (ANCA) reacting against myeloperoxidase (MPO-ANCA) are found in over 75% of the patients and are useful as a diagnostic tool (2,3). Untreated, systemic MPA follows a progressive course with a potentially fatal outcome caused by vital organ failure (4).

The combination of high dose corticosteroids (CS) and cyclophosphamide (CYC) is widely accepted as the standard therapy for patients with renal or lung involvement and has been reported to induce remission in 65 to 90% of patients (2,5–8). However, not all patients have a satisfactory response to CYC, and up to 50% of patients who respond to initial therapy experience a relapse within the first 3 to 5 years (5,7). In addition, CYC is associated with several serious acute and long-term adverse effects including bone marrow suppression, infection, infertility, secondary malignancies, and hemorrhagic cystitis, which result in treatment-related morbidity and mortality rivaling that caused by the underlying disease (9–12). Therefore, effective therapies that can avoid the CYC related toxicities have been sought.

Mycophenolate mofetil (MMF), which selectively inhibits lymphocyte proliferation, has been used in various immune-mediated nephritides (13–16). In ANCA-associated vasculitis (AAV), MMF has been evaluated as a remission maintenance agent or to induce remission in patients who have failed or are intolerant of CYC (17–20). Compared with CYC, the toxicity profile of MMF appeared superior, but disease activity control has been variable.

Several studies have suggested that MPA, particularly when associated with MPO-ANCA rather than PR3-ANCA, may have a lower mortality, less rapidly progressive renal disease, and a lower relapse rate than Wegener granulomatosis (WG) (8,21,22).

For all of these reasons, we designed a prospective pilot trial to evaluate the hypothesis that MMF can be used instead of CYC for remission induction and maintenance in patients with MPO-ANCA-positive MPA with mild to moderate renal involvement.

Materials and Methods

Trial Eligibility

This investigator-initiated trial was approved by the Institutional Review Board of the Mayo Clinic Rochester (Rochester, MN) and was registered on www.clinicaltrials.gov (identifier NCT00405860). Patients were eligible for enrollment if they fulfilled all of the following inclusion criteria: (1) clinical and histologic features compatible with the diagnosis of MPA according to the Chapel Hill Consensus definition (1); (2) positive for P-ANCA by immunofluorescence and MPO-ANCA by ELISA; (3) active renal involvement demonstrated by renal biopsy or, if biopsy was contraindicated, presence of active urinary sediment (red cell casts, or hematuria with >25 erythrocytes per high-powered field and dysmorphic red cells); and (4) serum creatinine ≤3.0 mg/dl. Exclusion criteria were (1) a diagnosis of WG; (2) positive C-ANCA/PR3-ANCA; (3) serum creatinine >3mg/dl or estimated GFR (eGFR) <20 ml/min; (4) organ compromise representing an immediate threat to the patient's life (e.g., pulmonary hemorrhage, cerebral involvement); (5) coexistence of another multisystem autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis); (6) the use of cytotoxic drug therapy in the last 6 months; (7) positive hepatitis B, C, or HIV serology; and (8) pregnancy or breastfeeding.

Definitions and Disease Assessments

Mild to moderate renal involvement was defined as having active GN (inclusion criterion #3) and a serum creatinine of ≤3 mg/dl (inclusion criterion #4 and exclusion criterion #3) at baseline.

Physical examinations and laboratory testing were conducted at baseline and weeks 2, 4, 8, 12, 24, 36, 48, 60, and 72. Serum creatinine and urinary protein/creatinine ratio was measured at each study visit. GFR was estimated using the four-variable Modification of Diet in Renal Disease equation (23). MPO-ANCA levels were assessed by direct ELISA (Phadia Diagnostics, Freiburg, Germany), and the P-ANCA pattern was confirmed by indirect immunofluorescence using ethanol-fixed neutrophil cytospin preparations according to the ANCA test algorithm used at our institution (24). Plasma levels of MMF metabolites mycophenolic acid (MA) and MA glucuronide were determined at each visit, with target blood levels of 1 to 3.5 μg/ml and 35 to 100 μg/ml, respectively. Chest roentgenograms were obtained at baseline and 18 months. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS)/WG instrument (25,26). Complete remission was defined as having a BVAS/WG score of 0. Any subsequent elevation in the BVAS/WG score of ≥1 point was considered a relapse. Major relapse was defined as recurrence or first appearance of a major BVAS/WG item such as scleritis, alveolar hemorrhage, peripheral neuropathy, active GN, or disease recurrence of sufficient severity to require treatment with high dose CS and CYC. Minor relapse was defined as recurrence of disease activity sufficient to warrant a transient increase in therapy but not severe enough to be classified as a major relapse and not threatening the function of a vital organ.

Treatment Protocol

Initial treatment consisted of 1 to 3 daily doses of methylprednisolone (1 g intravenously) followed by oral prednisone at a dose of 1 mg/kg per day (not exceeding 80 mg/d) for 2 weeks. Subsequently, the prednisone dose was reduced to 40 mg daily and tapered following a protocol that led to its complete discontinuation by month 6. MMF (CellCept) was started at an initial dose of 750 mg orally, twice daily, for the first week, and increased to 1000 mg twice daily in the second week according to patient tolerance. In patients who failed to respond to MMF at a dose of 1000 mg twice daily, the dose was increased to 1500 mg twice daily if tolerated. Minimum target blood levels of MMF metabolites and MA glucuronide were 1 to 3.5 or 35 to 100 μg/ml, respectively. The dose of MMF was adjusted according to tolerability and adverse events. However, it was not reduced if blood levels were above target in the absence of detectable side effects. MMF was continued for a total of 18 months. Patients who did not achieve remission or were unable to discontinue prednisone therapy according to schedule by 6 months were considered treatment failures as per protocol and were treated according to best medical judgment. Participation of patients in the trial ended at 18 months.

Concomitant Medications

The use of other immunosuppressive agents, anti-TNF agents, or intravenous gamma globulin was not permitted during the trial. Pneumocystis jiroveci pneumonia prophylaxis was mandatory for all patients. For prophylaxis of peptic ulceration, patients were placed on a proton pump inhibitor until prednisone was discontinued. Target blood pressure was <130/80 mmHg. Calcium channel blockers, diuretics, lipid-lowering agents, and warfarin were permitted during the study as needed, and their doses were adjusted to control hypertension, edema, or to keep the international normalized ratio in the therapeutic range. Angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor antagonists were continued if the patient had been on a stable dose for more than 4 weeks before entering the trial, but these drugs were not allowed to be started during the period of the study. Osteoporosis prophylaxis consisted of daily use of vitamin D, 800 IU, together with 1200 mg of calcium carbonate.

Outcomes

The primary outcome of the trial was remission rate at 6 months, defined by a BVAS/WG score of 0 and stable or falling serum creatinine levels. Treatment failure was defined as (1) inability to induce disease remission with combined use of prednisone and MMF necessitating treatment with another immunosuppressive agent, (2) inability to wean off prednisone because of persistent or progressive disease, and (3) inability to complete the full 18-month course of MMF because of treatment-related adverse events or disease relapse.

Statistical Analyses

Comparisons were performed with JMP version 7.0 (SAS, Cary, NC). Nonparametric paired analyses were performed to evaluate changes between baseline and follow-up visits for BVAS/WG and for laboratory values using Wilcoxon signed rank test. Results are expressed as mean ± SD or median (interquartile range). Statistical significance was taken at the P < 0.05 level.

Results

Demographic Characteristics and Disease Assessment at Baseline

Seventeen consecutive patients were enrolled between September 2003 and July 2007. The median age of the group was 64 years (range 40 to 86), 10 were men, and all were Caucasians. All patients were P-ANCA and MPO-ANCA positive at trial entry and had active disease, with a median BVAS/WG score of 7 (5 to 8). The disease was newly diagnosed in ten patients (58%). Five patients entered the trial at the time of their first relapse and two with their second relapse. The median (range) duration of symptoms was 15 months (6 to 55), and the time from diagnosis to enrollment was 0.2 months (0 to 43). The seven patients entering the trial with a relapse had previously received immunosuppressive therapy (three drugs in four patients, two drugs in one patient, and one drug in two patients). The cumulative dose of prednisone received by these patients was 8.2 g (6.3 to 9.4), of CYC 22 g (4.1 to 22.7) and of azathioprine 63 g (24.6 to 89.9).

Enrollment criteria mandated active renal disease at enrollment in all patients. This was confirmed by biopsy in 15 patients and by active urinary sediment in 2. The histologic findings of the renal biopsies were “focal and segmental necrotizing and crescentic glomerulonephritis” (n = 14) and isolated angiitis (n = 1). In one patient, no necrotizing or crescentic lesions were detected in the biopsy specimen, but red cells were present in the tubules, and red cell casts were found in the urine. Another patient could not be subjected to biopsy because of systemic anticoagulation. Details of the renal biopsy results of each patient are shown in Table 1. Active extrarenal organ manifestations were present in ten patients (Table 2).

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Table 1.

Renal biopsy results

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Table 2.

Organ manifestations of trial subjects before and at study enrollment

Clinical Outcomes

The primary outcome of remission at 6 months was achieved by 13 patients (76%). Four patients (24%) failed to achieve the primary outcome. Two of these did not respond to treatment, one experienced a major relapse, and one achieved remission but discontinued the study therapy because of gastrointestinal intolerance (Figure 1). Sustained remission until 18 months was maintained in 12 patients (70%). One patient relapsed at month 9. The cumulative BVAS/WG scores for all patients are shown in Figure 2A. Table 3 describes clinical details and management of patients who did not achieve the primary outcome or suffered a relapse.

Figure 1.
Figure 1.

Treatment response at different points of follow-up. Patients who met the primary endpoint of remission (BVAS/WG = 0) with stable or improved renal function, black; had persistently active disease (BVAS/WG persistently >0), gray; or were counted as treatment failures (relapse, lack of response, or intolerance of MMF), white.

Figure 2.
Figure 2.

Disease activity assessed by (A) BVAS/WG, (B) MPO-ANCA levels, (C) erythrocyte sedimentation rate, (D) C-reactive protein, (E) eGFR, and (F) proteinuria. Shown are the medians, interquartile range, and minimum/maximum values. The statistical analyses presented correspond to the comparisons between baseline and week 24 and between week 24 and the end of the trial (week 72). Data shown for each time point are based on patients remaining on protocolized therapy as indicated.

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Table 3.

Clinical manifestations and management of five patients who experienced treatment failure or relapse

Laboratory Results

There was an association between MPO-ANCA levels and clinical disease response (Figure 2B). The median MPO-ANCA levels decreased from 54 EU/ml (16 to 113) at baseline to 5 EU/ml (4 to 10) at week 24 (P < 0.01), and 5 EU/ml (3 to 10) at week 72 (P < 0.01) (reference range for negativity <5 EU/ml). All patients were ANCA positive at baseline, compared with 6 of 13 patients in remission at month 6 (46%, median 7.4 EU/ml) and 4 of 12 in remission at month 18 (33%, median 12 EU/ml). All four patients with major relapses were ANCA positive at the moment of relapse (median 39 EU/ml). The patient in whom MMF was discontinued because of intolerance remained in remission and ANCA negative. A total of nine patients became ANCA negative; all of these achieved disease remission. Of the eight patients who remained ANCA positive, four achieved complete remission (median MPO-ANCA of 27 EU/ml) and four experienced disease flares (median MPO-ANCA of 53 EU/ml).

Compared with baseline, the nonspecific markers of inflammation, erythrocyte sedimentation rate (Figure 2C) and C-reactive protein (Figure 2D) showed significant decreases as early as two weeks after enrollment, which were maintained for the duration of the trial. The median erythrocyte sedimentation rate dropped from 38 mm/h (24 to 73) at baseline to 9 mm/h (5 to 10) (P < 0.01) at week 72, and the median C-reactive protein dropped from 0.5 mg/dl (0.3 to 5.3) to 0.3 mg/dl (0.3 to 0.4).

Renal outcomes assessed by eGFR and proteinuria are shown in Figure 2, E and F, respectively. The eGFR remained stable during the first 6 months (baseline 46 ml/min (34 to 63) versus 47 ml/min (33 to 72) at week 24, P = NS). Beyond 6 months, the eGFR gradually increased and reached 52 ml/min/m2 (35 to 67) at week 72 (P < 0.05). Continued follow-up of the 12 patients who were in remission at 18 months showed further improvement of eGFR to 57 ml/min/m2 (36 to 95) at 24 months.

Proteinuria decreased from 889 mg/24 h at baseline (400 to 2208) to 384 mg/24 h at week 24 (151 to 1071; P < 0.01) and further to 149 mg/24 h at week 72 (36 to 561; P < 0.001). Eight of the patients were on treatment for hypertension before enrollment into the study. Three of these were on treatment with an ACEi and one was treated with an ACEi and an angiotensin II receptor blocker. No patient was newly diagnosed with hypertension during the trial. Blood pressure control actually improved in most patients, and at 18 months only one patient remained on ACEi therapy. Thus, the observed reduction in proteinuria cannot be attributed to blockade of the angiotensin II system.

MMF metabolite levels and corresponding drug doses are shown in Table 4. The median values of MA were slightly above the reference range (1 to 3.5 μg/ml) during the first 6 months and at or above the reference range during the remainder of the study. The median plasma levels of MA glucuronide were within the reference range for the duration of the study (35 to 100 μg/ml). Plasma levels of both decreased with the reduction in the MMF dose. There was no correlation between MA or MA glucuronide levels and the clinical response to MMF or the presence of side effects.

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Table 4.

Plasma levels of MMF metabolites, MA, MA glucuronide, and treatment doses for each follow-up visit

Side Effects

MMF was associated with detectable side effects in ten patients (58%). These were mild and included gastrointestinal upset (diarrhea, nausea, or bloating) in six patients, mild leucopenia (total white cell count between 3000 and 4000/mm3) in three, headache in one, and weakness in one. These side effects could be managed by dose reduction except in one patient who could not tolerate MMF even at reduced dose. One patient developed avascular necrosis of the hip that was attributed to the use of CS. One minor respiratory tract infection treated with a 1-week course of oral antibiotics was observed.

Discussion

The results of this pilot trial indicate that MMF in combination with CS can be used successfully and safely for induction of remission in patients with MPO-ANCA-positive MPA with mild to moderate renal involvement. The efficacy of MMF for induction of remission in this homogeneous patient population is comparable to what has been reported for CYC. MMF without CS also appeared to be effective and well tolerated for maintenance of remission in this patient population.

The most widely accepted standard treatment for remission induction of patients with severe AAV consists of the combined use of CS and CYC. The evidence for this practice is derived from several uncontrolled trials. The exact efficacy of CYC for remission induction in MPA is difficult to estimate from these studies for various reasons. First, remission induction trials in AAV include only a minority of patients with MPA or MPA is studied together with other forms of vasculitis such as polyarteritis nodosa and Churg-Strauss syndrome (7,8,27). Yet, it is recognized that the clinical course and prognosis of WG, polyarteritis nodosa, and Churg-Strauss syndrome differ from that of MPA. Second, the use of low-dose CS maintenance therapy is not consistent across studies, and some authors feel that this factor affects observed remission rates (28). Third, the definitions of remission vary between different trials. For instance, in contrast to our study, some trials allow one persistent minor BVAS item during remission (8). Finally, the disease severity of MPA varies highly between different reports. The study with the poorest outcome in response to therapy with CS and CYC comes from Korea and reports an initial response rate of 65% but a mortality rate of 56% among 18 patients with MPO-ANCA-associated MPA (29). These patients had a high prevalence of diffuse alveolar hemorrhage, which has been identified as a marker of poor prognosis in MPA (22). On the basis of the available efficacy data for CYC, the best estimate is that 65% to 90% of patients with MPA will achieve remission with daily oral or intravenous pulse application of CYC in combination with CS. The observed remission rate of 76% achieved with MMF in our well defined MPA study population falls into that range.

Several other reports of MMF used as a remission induction agent or for remission maintenance in AAV have been published since initiation of our trial (Table 5). These studies differ from our trial design in many aspects. The report comprising the most patients is a retrospective review of the off-label use of MMF for remission induction or maintenance in AAV; it comprises 16 patients with MPA (30). The two uncontrolled open-label trials of MMF for remission induction in AAV contain only two and three patients with MPA, respectively; most of the enrolled patients had WG (19,20). Furthermore, these studies only enrolled patients who were either relapsing, resistant to CYC, or had contraindications for CYC use (19,20). In contrast, our trial focused solely on patients with MPO-ANCA-positive MPA with active renal disease, and most enrolled patients were newly diagnosed and CYC naive. Despite these differences, our observed remission rate of 76% and the mean time to remission of 2.1 months were comparable to those of the other studies (Table 5).

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Table 5.

Published studies of MMF in AAV

Since completion of our trial, one randomized controlled trial has been reported that compared the efficacy of MMF for remission induction to intravenous bolus CYC in Chinese patients with active AAV and serum creatinine <5.6 mg/dl (31). A total of 35 patients were randomized to receive MMF (n = 18) or CYC (n = 17). Of the 35 patients, 28 were MPO-ANCA positive, 2 were PR3-ANCA positive, and 5 were ANCA negative. Patients in both groups initially received intravenous methylprednisolone pulse therapy (0.5 g, once daily, for 3 consecutive days), followed by oral prednisone, which was then tapered to 10 mg/d at month 6. In the MMF group, MMF was given at a dose of 1.5 to 2.0 g/d for 6 months. The reported remission induction rate achieved with MMF in that trial was similar to ours (77.8%) (31). However, the follow-up was restricted to 6 months, with only 8 of 18 patients (44.4%) in the MMF group and 2 of 17 patients (15.4%) in the CYC group recovering renal function.

Earlier reports, which focused solely on MMF as a remission maintenance agent, were conducted in patients with WG rather than MPA (17,18) (Table 5). Because WG is more likely to relapse than MPA, it is not unexpected that the reported relapse rates of those cohorts were higher than observed in our trial (8,17,18).

It is encouraging that remission could be induced very effectively with MMF in this patient population and that only 1 of 13 patients who achieved the primary endpoint had a relapse before 18 months. Control of disease activity is a crucial prerequisite for good clinical outcomes in AAV. However, preservation or improvement of renal function is also very important because renal function after treatment is an important determinant of long-term renal survival and quality of life (32,33). Our findings that renal function and proteinuria improved in the patient group as a whole suggest that MMF treatment of patients with MPA and renal involvement may also have a beneficial effect on long-term renal survival.

The success rate observed in our study is unlikely to be simply the result of the selection bias inherent to recruiting a subset of patients with mild disease that could have been treated with oral CS alone. Nachman and coworkers have shown that even in patients with MPA and mild renal disease, therapy with CS alone is associated with an unacceptably poor treatment outcome (5). The remission rate was only 56% compared with 85% (P = 0.003) in patients treated with the combination of CS and CYC (5). Similarly, patients who only received CS had a 3-fold higher risk of relapse than those treated with combined CS and CYC (5).

MMF was well tolerated by most trial participants. Gastrointestinal side effects could be managed by dose modifications in all patients except one, who had to discontinue MMF because of intolerance. Similarly, mild leucopenia was successfully managed by dose reduction. No severe infections were encountered. We attribute this remarkable absence of infection to the rapid CS taper, careful follow-up, and the use of antibiotic prophylaxis in all patients. The observed favorable adverse events profile is consistent with reports of MMF use in transplantation and other autoimmune renal disease (16,34,35).

Our study has several limitations. First, the number of patients enrolled into our trial is small. Nevertheless, only the randomized 6-month remission induction trial from China contained a similar number of patients with MPA treated with MMF (31). Second, one of the strengths of our study, the selected homogeneous patient population, is also a limitation: although our remission induction rate is comparable to what others have reported in cohorts where WG was over-represented, the results of our study should not be extrapolated to all patients with AAV, particularly not those with alveolar hemorrhage, vasculitis-related neuropathy, and possibly those with PR3-ANCA. Third, our trial was uncontrolled. Nevertheless, our trial had protocol-defined time points of assessments and outcomes, utilized a validated instrument for the assessment of disease activity, all patients were given a protocolized CS tapering regimen, and the long-term follow-up of 18 months followed the standard applied to large randomized trials in AAV. Given these qualities, our data still provide guidance about what to expect from MMF use in MPO-ANCA-positive MPA.

In conclusion, our results clearly indicate that MMF should be considered as an effective and well tolerated alternative to CYC for remission induction in non-life-threatening MPO-ANCA-positive MPA with mild to moderate renal involvement. MMF also seems effective and safe as monotherapy for remission maintenance in such patients. Consequently, MMF is a serious contender deserving further study in a randomized controlled trial comparing it to CYC or other agents in this patient population. The data from our pilot trial provide significant information for the design of such a larger trial.

Disclosures

None.

Acknowledgments

The authors are indebted to Shirley Jennison and Catherine A. Erding who were the study coordinators for the trial. This study was supported by an unrestricted research grant from Roche Laboratories Inc., Nutley, New Jersey. Dr. Silva was supported in part by a fellowship from the Vasculitis Clinical Research Consortium (by grant U54 RR019497) and by funds from the Mayo Foundation.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Received August 25, 2009.
  • Accepted December 17, 2009.

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Mycophenolate Mofetil for Induction and Maintenance of Remission in Microscopic Polyangiitis with Mild to Moderate Renal Involvement—A Prospective, Open-Label Pilot Trial
Francisco Silva, Ulrich Specks, Sanjay Kalra, Marie C. Hogan, Nelson Leung, Sanjeev Sethi, Fernando C. Fervenza
CJASN Mar 2010, 5 (3) 445-453; DOI: 10.2215/CJN.06010809
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